Case Discussion A 64-year old woman diagnosed with monoclonal gammopathy of undetermined significance (MGUS) in September 2015 She has been monitored over time and has had a slight increase in her proteins. There was no evidence of end-organ damage, and her PET scan was negative.

Indications for Considering Treatment (IMWG Consensus Guidelines) At least 1 of the CRAB Criteria (evidence of end-organ damage) CRAB criteria Hypercalcemia Serum calcium >2.75 mmol/L (>11 mg/dL) Renal failure Serum creatinine >2 mg/dL or creatinine clearance <40 mL per min Anemia Hb >2.0 g/dL below the lower limit of normal or a hemoglobin value <10.0 g/dL Bone ≥1 osteolytic lesions on skeletal radiography, CT or PET-CT New myeloma defining events: The biomarkers ≥60% clonal bone marrow plasma cells Serum involved/uninvolved free light chain ratio ≥100 >1 focal bone lesion on MRI Rajkumar SV et al. ASCO 2016 Education Session.

QuiRedex Trial of Len/Dex in High-Risk SMM Phase III study of len/dex vs observation for pts with high-risk smoldering MM Efficacy Len/dex (n = 57) Observation (n = 62) HR, p-value Median time to progression Not reached 23 mo 0.24, <0.0001 Median OS 0.43, 0.024 Mateos MV et al. Lancet Oncol 2016;17:1127-36.

Phase II Trial of Elo/Len/Dex in High-Risk Smoldering MM PFS ≥PR = 19/23 (82.6%); CR + VGPR + PR + MR = 23/23 (100%) Subsequent to this interview, these data were presented at ASH 2016 With permission from Ghobrial IM et al. Proc ASH 2016;Abstract 976.

Case Discussion An 87-year-old man initially diagnosed with smoldering myeloma 2 years earlier Presents with lytic bone disease and anemia and is considered to have symptomatic multiple myeloma

Case Discussion An 87-year-old man is initially diagnosed with smoldering myeloma Presents 2 years later with lytic bone disease and anemia and is then considered to have symptomatic multiple myeloma He receives RVd-lite  lenalidomide maintenance and is currently in a CR

TOURMALINE MM2: A Phase III Trial of Ixazomib/Len/Dex vs Len/Dex for Newly Diagnosed MM NCT01850524 Ixazomib + lenalidomide + dexamethasone Enrollment (n = 701) Newly diagnosed MM Not eligible for stem cell transplant R Placebo + lenalidomide + dexamethasone Primary endpoint: PFS www.clinicaltrials.gov. Accessed June 2017

TOURMALINE-MM1: Oral Ixazomib with Len/Dex for MM Phase III trial of pts with relapsed/refractory MM treated with ixazomib and lenalidomide/dex (ixazomib group) or placebo and lenalidomide/dex (placebo group) Efficacy Ixazomib group (n = 360) Placebo group (n = 362) HR, p-value Median PFS 20.6 mo 14.7 mo 0.74, 0.01 ORR 78% 72% —, 0.04 Median overall survival: not reached in either group Moreau P et al. N Engl J Med 2016;374(17):1621-34.

SWOG S0777: VRd versus Rd for Newly Diagnosed MM Phase III study of VRd versus Rd for pts with newly diagnosed MM without intent for immediate ASCT Outcome VRd Rd HR, p-value Median PFS (n = 242, 229) 43 mo 30 mo 0.712, 0.0018 Median OS (n = 242, 229) 75 mo 64 mo 0.709, 0.025 ORR (n = 216, 214) 81.5% 71.5% — Durie B et al. Lancet 2017;389:519-27.

IFM 2009 Trial: RVD with Transplant versus RVD Alone for Newly Diagnosed MM Phase III study of patients with transplant-eligible, newly diagnosed MM Treatment: RVD with transplant versus RVD alone followed by len maintenance (1 y) Outcome Transplant (n = 350) RVD HR, p-value Median PFS 50 mo 36 mo 0.65, <0.001 Overall survival (4 y) 81% 82% 1.16, 0.87 Response Complete response Partial response 59% 11% 48% 20% —, 0.03 Attal M et al. N Engl J Med 2017;376(14):1311-20.

PFS (3 y) in pts achieving CR Predictive Value of Minimal Residual Disease (MRD) in the IFM 2009 Trial Bone marrow MRD evaluation (pre- and postmaintenance) in patients with ≥VGPR Prediction of PFS by MRD status as determined by NGS (Patients in CR) PFS (3 y) in pts achieving CR MRD-negative (<10-6) MRD-positive (≥10-6) Premaintenance 87% 63% Postmaintenance 92% 64% Avet-Loiseau H et al. Proc ASH 2015;Abstract 191.

DETERMINATION: A Phase III Trial of RVD with or without ASCT for Newly Diagnosed MM NCT01208662 Estimated enrollment (n = 660) Newly diagnosed MM ≤65 y R RVD + ASCT Patients in both arms will receive lenalidomide maintenance until disease progression Primary endpoint: PFS www.clinicaltrials.gov. Accessed June 2017

Case Discussion A 76-year-old man diagnosed with multiple myeloma in 2006 Progressed through multiple lines of therapy including lenalidomide/dexamethasone (dex) and ixazomib/lenalidomide/dex Received daratumumab plus pomalidomide/dex in June 2016 and is faring well

Management of Daratumumab-Associated Infusion-Related Reactions “For a busy oncology practice in the community, I always say there’s two things that people are doing. One is: They’re splitting doses. But probably the most important one is: Just give as much as you can on Day 1, and you’re going to flush some of that reaction. So by the time you get to the second week – and it’s true with most of the monoclonals – then you tend not to have reactions. So it’s just Day 1 that needs to be managed.” Dr Rafael Fonseca

POLLUX: A Phase III Trial of Daratumumab/Len/ Dex for Relapsed/Refractory MM Patients with MM (n = 569) who had received 1 or more prior therapies received daratumumab and len/dex (DRd) or len/dex (Rd) Efficacy DRd (n = 286) Rd (n = 283) HR, p-value Median PFS PFS (12 mo) Not reached 83.2% 18.4 mo 60.1% 0.37, <0.001 Overall response rate 92.9% 76.4% —, <0.001 Most common Grade 3/4 adverse events: neutropenia, thrombocytopenia, anemia Daratumumab-associated infusion-related reactions reported in 47.7% of patients, mostly Grade 1/2 Dimopoulos MA et al. N Engl J Med 2016;375(14):1319-31.

Phase III CASTOR Trial of Daratumumab and Bortezomib/Dex for Relapsed/Refractory MM Patients with relapsed/refractory MM (n = 498) received bortezomib/dex (Rd) alone or in combination with daratumumab (DVd) Efficacy DVd (n = 251) Vd (n = 247) HR, p-value Median PFS PFS (12 mo) Not reached 60.7% 7.2 mo 26.9% 0.39, <0.001 Overall response rate 82.9% 63.2% —, <0.001 Most common Grade 3/4 adverse events: neutropenia,  thrombocytopenia, anemia Daratumumab-associated IRRs: 47.7% of patients, mostly Grade 1/2 Palumbo A et al. N Engl J Med 2016;375:754-66.

Case Discussion A 45-year-old man who was diagnosed 4 years ago with MM Received RVD with transplant followed by len maintenance for 18 mo Progressed with bone disease and received radiation therapy and carfilzomib/pomalidomide/dex and achieved a VGPR

Case Discussion A 45-year-old man who was diagnosed 4 years ago with MM Received RVD with transplant followed by len maintenance for 18 mo Progressed with bone disease and received radiation therapy and carfilzomib/pomalidomide/dex and achieved a VGPR Experienced relapse again, received daratumumab/len/ dex and has achieved a PR

POLLUX and CASTOR Trials of Daratumumab for Relapsed/Refractory MM Efficacy DRd (n = 286) Rd (n = 283) HR, p-value Median PFS Not reached 18.4 mo 0.37, <0.001 Overall response rate 92.9% 76.4% —, <0.001 CASTOR Efficacy DVd (n = 251) Vd (n = 247) HR, p-value Median PFS Not reached 7.2 mo 0.39, <0.001 Overall response rate 82.9% 63.2% —, <0.001 Dimopoulos MA et al. N Engl J Med 2016;375(14):1319-31. Palumbo A et al. N Engl J Med 2016;375:754-66.

PAVO: A Phase Ib Study of Subcutaneous Daratumumab (DARA) for Relapsed/Refractory MM Patients with relapsed/refractory MM (n = 41) received 1,200 mg and 1,800 mg subcutaneous DARA in combination with human hyaluronidase enzyme (rHuPH20) to facilitate absorption. Preliminary data suggest that subcutaneous DARA-PH20 may enable similar response rates to IV DARA monotherapy. At the 1,800-mg dose of DARA-PH20, overall response rate: 41% Infusion-related reactions (IRRs) were reported in 9/41 pts (22%) and were mostly Grade 1/2. All IRRs developed ≤6 h of the first SC infusion and were controlled with antihistamines, corticosteroids, antiemetics or a bronchodilator. Subsequent to this interview, these data were presented at ASH 2016 Usmani SZ et al. Proc ASH 2016;Abstract 1149.

Venetoclax (VEN) for Relapsed/Refractory MM Phase I study of VEN monotherapy for pts with relapsed/refractory MM Efficacy All pts (n = 66) t(11;14) No t(11;14) Overall response rate ≥VGPR 21% 15% 40% 27% 6% Median time to progression 2.6 mo 6.6 mo 1.9 mo Grade 3/4 hematologic AEs: thrombocytopenia (32%), neutropenia (27%), anemia (23%), leukopenia (23%) No TLS events reported Kumar S et al. Proc IMW 2017;Abstract 129.

Venetoclax with Bortezomib/Dex for Relapsed/Refractory MM Phase Ib study of pts with relapsed/refractory MM treated with venetoclax/bortezomib/dex Response All pts (n = 65) BTZ nonrefractory (n = 44) BTZ refractory (n = 21) Overall response rate 68% 89% 24% Stringent CR 5% 7% 0% CR 12% 18% VGPR 23% 32% PR 28% 19% Moreau P et al. Proc ASH 2016;Abstract 975.

Phase II Study of Pembrolizumab/Pomalidomide/ Dex for Relapsed/Refractory MM Response ITT (n = 48) Double refractory (n = 32) High risk (n = 27) ORR 60% 66% 56% sCR/CR 8% 4% 11% VGPR 19% 18% PR 33% 44% 41% Median follow-up = 15.6 mo Median duration of response = 14.7 mo Badros AZ et al. Proc ASH 2016;Abstract 490; Badros A et al. Blood 2017;[Epub ahead of print].

KEYNOTE-023: Pembrolizumab/Lenalidomide/ Dex for Relapsed/Refractory MM Phase I study of pembrolizumab with lenalidomide/dex N = 34 patients with R/R MM after disease progression on ≥2 prior therapies Objective response rate: – All evaluable patients: 13/17 (76%) – Lenalidomide-refractory disease: 5/9 (56%) Few low-grade immune-related adverse events San Miguel et al. Proc ASH 2015;Abstract 505.

Response to CAR-BCMA T-Cell Therapy and Adverse Events Pts with advanced relapsed/refractory MM enrolled: n = 12 Method: Single infusion of anti-BCMA CAR T cells after a 3-day regimen of cyclophosphamide/fludarabine CAR-BCMA T cells eliminated plasma cells without direct organ damage. Significant antimyeloma responses were associated with the highest levels of CAR-BCMA T cells in the blood. Toxicites consistent with cytokine release syndrome (including fever, hypotension and dyspnea) were substantial but reversible. Ali SA et al. Blood 2016;128(13):1688-700. Proc ASH 2015;Abstract LBA-1.